Many types of mass spectrometers are known, and are widely used for trace analysis to determine the structure of ions. These spectrometers typically separate ions based on the mass-to-charge ratio (“m/z”) of the ions.
For example, a tandem mass spectrometer might include a mass selection section, followed by a fragmentation cell, and then a further mass resolving section. Typically in MS/MS analysis, one precursor or parent ion would be selected in the first mass selection section. The rest of the ions would be rejected in this first mass selection section. Then, this parent or precursor ion of interest would be fragmented in the fragmentation cell. These fragments are then provided to a downstream mass resolving section in which a particular fragment of interest is selected. The remainder of the fragments would typically be rejected.
This approach is inefficient when tandem mass spectrometry is used to analyze a mixture of analyte substances. That is, when one type of ion is selected as a precursor for MS/MS experiments, ions representing other substances in the mixture will be filtered out and lost. If these ions representing other substances are also of interest, then it will be necessary to run subsequent MS/MS analysis focused on these other ions of interest, thereby increasing the time and expense of conducting these experiments.
Another mode of operation of tandem mass spectrometry is called “a precursor ion scan”. In this mode of operation, the filtering window between an initial rod section and a downstream fragmentation cell is varied slowly to selectively admit precursor ions. Each of these precursor ions can than be fragmented in the fragmentation cell, and subjected to further mass analysis downstream of the fragmentation cell by other MS/MS instruments as required, to generate fragmentation spectra. From these fragmentation spectra generated for different ions, a desired fragmentation spectrum can be identified. Again, however, in this mode of operation, efficiency is quite low as most of the ions are filtered out. For example, if the filtering window is 1 Thomson, and the scanning interval is 1000 Thomson, then overall efficiency of the instrument will drop by a factor of 1000 in comparison to an MS/MS experiment for a single precursor ion of interest. Accordingly, MS/MS operation will be substantially improved in terms of both sensitivity and efficiency if all of the ions representing different components of a mixture can be stored and introduced into a fragmentation stage on a selective basis without the efficiency losses described above.
Tandem mass spectrometers may also include upstream quadrupole mass analyzers, in which RF/DC ion guides are used to transmit ions within a narrow range of m/z values to downstream “time-of-flight” (“TOF”) analyzers, in which measuring the flight time over a known path for an ion allows its m/z to be determined.
Unlike quadrupole mass analyzers, TOF analyzers can record complete mass spectra without the need for the scanning parameters of a mass filter, thus providing a better duty cycle and a higher acquisition rate (ie. a more rapid turnaround in the analysis process). In certain mass spectrometers, RF ion guides are coupled with orthogonal TOF mass analyzers where the ion guide is for the purpose of transmitting ions to the TOF analyzer, or is used as a collision cell for producing fragment ions and for delivering the fragment ions (in addition to any remaining parent ions) to the TOF analyzer. Combining an ion guide with the orthogonal TOF analyzer is a convenient way of delivering ions to a TOF analyzer for analysis.
It is presently known to employ at least two modes of operation of orthogonal TOF mass spectrometers employing ion guides.
In the first mode, a continuous stream of ions leaves a radio-frequency-only quadrupole ion guide comprising a collision cell and a mass filter and is directed to an extraction region of the TOF analyzer. The stream is then sampled by TOF extraction pulses for detection in the normal TOF manner. This mode of operation has duty cycle losses as described, for example, in a tutorial paper by Chernushevich et al., in the Journal of Mass Spectrometry, 2001, Vol. 36, 849–865, (“Chernushevich et al.”).
The second mode of operation is described in Chernushevich et al., as well as in U.S. Pat. No. 5,689,111 and in U.S. Pat. No. 6,285,027. This mode involves pulsing ions out of a two-dimensional ion guide such that ions having particular m/z values (i.e., m/z values within narrowly-defined ranges) are bunched together in the extraction region of the TOF. This mode of operation reduces transmission losses between the ion guide and the TOF, but due to the dependence of ion velocity on the m/z ratio only ions from a small m/z range can be properly synchronized, leading to a narrow range of m/z (typical mmax/mmin ˜2) that can be effectively detected by the TOF analyzer. Thus, when ions with a broad range of masses have to be recorded, it is necessary to transmit multiple pulses having parameters specific to overlapping m/z ranges in order to record a full spectrum. This results in inefficiencies since ions outside the transmission window are either suppressed or lost. One way to avoid this loss is proposed in commonly assigned U.S. Pat. No. 6,744,043. In this patent, an ion mobility stage is employed upstream of the TOF analyzer. The mobility migration time of the ions is somewhat correlated with the m/z values of the ions. This allows for adjustment of TOF window in pulsed mode so that the TOF window is always tuned for the m/z of ions that elute from the ion mobility stage. However, addition of the mobility stage to the spectrometer apparatus increases the complexity and cost of the apparatus. Moreover, the use of pulsed ejection and corresponding continual adjustment of the TOF window prevents optimal efficiencies in cycle time, or process turnaround, for the spectrometer.